Diisopropylethylamine → HCID 66823801, compound

Participants

Reaction Steps

To a stirred dark greenish solution of 5-(2,3-dihydro-1H-indol-5-yl)furo[2,3-d]pyrimidin-4-amine (500 mg, 1.98 mmol) and HATU (829 mg, 2.18 mmol, 1.1 equiv) in 5 mL of DMF was added DIEA (381 uL, 2.18 mmol, 1.1 equiv). To this mixture was added (3-chloro-5-fluorophenyl)acetic acid portionwise (374 mg total, 1.98 mmol, 1 equiv), about 130 mg at 30 min intervals. After 2 h, LCMS showed conversion complete. The mixture was poured into 50 mL of ice cold water to give a suspension, which was filtered. The cake was washed with water (2×10 mL) and dried under house vacuum for 18 h to afford crude product (1.0 g), which was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an SF25-60 g silica gel cartridge using gradient elution of 1% A in DCM to 50% A in DCM (A was a mixture of 3200/800/80 DCM/MeOH/NH4OH). The desired product eluted impure from 24-30% A. The fractions containing product were combined and concentrated in vacuo and reabsorbed onto a dryload cartridge. Purification was done on an SF25-80 g silica gel cartridge using gradient elution of 1% A to 75% A in EtOAc. (B was a 2.5% MeOH in EtOAc). Two fractions were collected. The first fraction eluted from 15-35% B as a sharp peak, which was conc in vacuo. The residue was taken up in CHCl3 (2 mL) and MTBE (6 mL) as a suspension, which was filtered. The solids were washed with MTBE (2×3 mL) and hexane (2×3 mL). The second fraction eluted from 63-100% B as a broad. The large eluted solvent volume was concentrated in vacuo. This residue was taken up in CHCl3 (2 mL) and MTBE (8 mL) as a suspension, which was filtered. The cake was washed with MTBE (2×3 mL) and hexane (3×4 mL). The solids were combined with the solids above from the first fraction and dried under vacuum at 65° C. for 18 h to afford 5-{1-[(3-chloro-5-fluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[2,3-d]pyrimidin-4-amine (492 mg) as off-white solids. LC-MS (ES) m/z=423 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d ppm 3.26 (t, J=8.3 Hz, 2H), 3.97 (s, 2H), 4.25 (t, J=8.5 Hz, 2H), 7.18 (d, J=9.9 Hz, 1H), 7.27 (s, 1H), 7.29-7.38 (m, 2H), 7.39 (s, 1H), 7.93 (s, 1H), 8.15 (d, J=8.1 Hz, 1H), 8.25 (s, 1H), NH2 protons not visible.

Provenance & Evidence